Allophanic acid derivatives

ABSTRACT

The invention concerns allophanic acid derivatives of formula I 
     
         R.sup.1 --N(R.sup.2)CO--N(R.sup.3)CO--X.sup.1 --Q--X.sup.2 --GI 
    
     and pharmaceutically acceptable metabolically labile esters or amides thereof, and pharmaceutically acceptable salts thereof, in which R 1 , R 2 , R 3 , X 1 , Q X 2  and G have the meanings given in the specification. The invention also concerns processes for the preparation of the allophanic acid derivatives of formula I, pharmaceutical compositions containing them and their use as inhibitors of the binding of fibrinogen to glycoprotein IIb/IIIa.

This is a divisional of application Ser. No. 08/365,761 filed Dec. 29,1994 which is a continuation of application Ser. No. 08/266,454 filedJun. 27, 1994 (now abandoned).

The present invention relates to a group of chemical compounds whichinhibit cell adhesion (for example platelet aggregation), to processesfor their preparation and to pharmaceutical compositions containingthem.

A variety of diseases involve cell adhesion during their development.For example, platelet aggregation is involved in the formation of bloodthrombi, which can lead to diseases such as thrombosis, (for examplestroke and thrombotic events accompanying unstable angina and transientischaemic attack), myocardial infarction, atherosclerosis,thromboembolism and reocclusion during and after thrombolytic therapy.

It is widely believed that the platelet membrane glycoprotein IIb-IIIa(GPIIb-IIIa) mediates platelet aggregation. Adhesion molecules such asfibrinogen and yon Willebrand Factor are believed to bind to GPIIb-IIIasites on adjacent platelets and thereby cause them to aggregate. Otheradhesion molecules which are known to bind to GPIIb-IIIa arefibronectin, vitronectin and thrombospondin.

Compounds which inhibit platelet aggregation and the binding of adhesionmolecules to GPIIb-IIIa are known, for example from U.S. Pat. Nos.5,039,805 and 5,084,446, Canadian patent applications numbers 2,008,161,2,037,153 and 2,061,661, and Alig et al., J. Med. Chem., 1992, 35,4393-4407. Commonly the structures of these compounds are based upon thebinding regions of the adhesion molecules, which are peptides. Forexample, a portion of fibrinogen which is believed to bind to GPIIb-IIIais the amino acid sequence RGD (arginyl glycyl aspartate).

The ability to inhibit platelet aggregation and to inhibit the bindingof fibrinogen to GPIIb-IIIa has now been found to be possessed bycertain acid derivatives containing an allophanoyl group.

According to one aspect, therefore, the present invention provides acompound of the general formula I (formula set out at the end of thedescription together with the other formulae referred to herein by Romannumerals) wherein R¹ represents a group of formula II or III in which

A is attached meta or para to the position where the group NR² CONR³ COis attached and is selected from aminomethyl, guanidino and

R^(a) N═C(NH₂)-- where R^(a) is hydrogen or phenyl which isunsubstituted or substituted by 1 or 2 of halogeno, (1-4C)alkyl,(1-4C)alkoxy, cyano and nitro,

E is CH or N,

Z¹ is hydrogen, halogeno, (1-4C)alkyl, (1-4C)alkoxy, cyano or nitro,

T is N or CH, and

X³ is a bond, (1-4C)alkylene or, when T is CH, oxy(1-3C)alkylene;

R² and R³ which may be the same or different, represent hydrogen,(1-4C)alkyl or ar(1-4C)alkyl;

X¹ is a bond or (1-4C)alkylene;

Q is a group of formula IV or V in which Z² is hydrogen, halogeno,(1-4C)alkyl, (1-4C)alkoxy, cyano or nitro, and

Z³ is a group of formula X² --G^(a) in which X² can have any of thevalues given hereinafter for X² and G^(a) can have any of the valuesgiven hereinafter for G, or G^(a) has any of the values givenhereinbefore for Z² ;

X² is a bond, (1-4C)alkylene, oxy(1-3C)alkylene or a group of formulaCH₂ CH(NHXR⁴) in which X is SO₂, CO or CO₂ and R⁴ is (1-6C)alkyl,(6-12C)aryl or (6-12C)aryl(1-4C)alkyl, in any of which the aryl groupmay optionally be substituted by (1-4C)alkyl; and

G is a carboxy group or a pharmaceutically acceptable metabolicallylabile ester or amide thereof; and

pharmaceutically acceptable salts thereof.

It will be appreciated that depending on the nature of the substituents,in containing one or more chiral centres, the formula I compounds mayexist in and be isolated in one or more different enantiomeric orracemic forms (or a mixture thereof). It is to be understood that theinvention includes any of such forms which possesses the property ofinhibiting platelet aggregation and inhibiting the binding of fibrinogento GpIIb-IIIa, it being well known how to prepare individualenantiomeric forms, for example, by synthesis from appropriate chiralstarting materials or by resolution of a racemic form. Similarly, thebiological properties of a particular form may be readily evaluated, forexample by use of one or more of the standard in vitro or ex vivoscreening tests detailed hereinbelow.

It will also be appreciated that compounds of formula I wherein R¹represents a group of formula II and A represents the group R^(a)N═C(NH₂)-- may exist in tautomeric forms, and that the inventionincludes the compounds in any of their tautomeric forms.

A is preferably a group of formula R^(a) N═C(NH₂)--. It is preferablyattached para to the position where the group NR² CONR³ CO is attached.

Examples of values for Ra include hydrogen and phenyl. Examples ofsubstituents on R^(a) when it is phenyl include fluoro, chloro, bromo,methyl, ethyl, methoxy, ethoxy, cyano and nitro.

When R¹ represents a group of formula II bearing the substituent Z¹, Z¹may represent, for example hydrogen fluoro, chloro, bromo, methyl,ethyl, methoxy, ethoxy, cyano or nitro.

When R¹ represents a group of formula III examples of values for X³include a bond, methylene, ethylene, trimethylene and, when T is CH,oxymethylene.

Examples of values for R¹ include 3-aminomethylphenyl,4-aminomethylphenyl, 4-amidinophenyl, 4-(N² -phenyl)amidinophenyl,6-amidinopyrid-3-yl, 5-amidinopyrid-2-yl, piperidin-4-yl,piperidin-4-ylmethyl, 2-piperidin-4-ylethyl, piperidin-4-yloxymethyl andpiperazin-1-yl.

A (1-4C)alkyl group represented by R² or R³ may be, for example, methylor ethyl. An ar(1-4C)alkyl may be, for example, benzyl. Preferably oneof R² and R³ is hydrogen and the other is hydrogen, methyl or benzyl.More preferably each of R² and R³ represents hydrogen.

Examples of values for X¹ when it represents (1-4C)alkylene aremethylene and ethylene. Preferably X¹ represents a bond.

In the group Q, when it is a group of formula IV, examples of values forZ² include hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy,ethoxy, cyano and nitro. Hydrogen is a preferred value for Z².

In the group Q, when it is a group of formula IV or V, and Z³ is a groupof formula X² --G¹, examples of values for X² include a bond, methylene,ethylene, oxymethylene and groups of formula CH₂ CH(NHXR⁴) in which X isSO₂, CO or CO₂ and R⁴ is methyl, ethyl, propyl, butyl, pentyl, phenyl,tolyl or benzyl, and examples of values for G^(a) include carboxy (or apharmaceutically acceptable metabolically labile ester or amidethereof), hydrogen, fluoro, chloro, bromo, methyl, ethyl, methoxy,ethoxy, cyano and nitro. Preferably Z³ is hydrogen or a group of formulaX² -G^(a) in which X² is oxymethylene and G^(a) is carboxy.

Examples of values for X² include a bond, methylene, ethylene,oxymethylene, oxyethylene and groups of formula CH₂ CH(NHXR⁴) in which Xis SO₂, CO or CO₂ and R⁴ is methyl, ethyl, propyl, butyl, pentyl,phenyl, tolyl or benzyl. Preferably X² is oxymethylene or a group offormula CH₂ CH(NHSO₂ (CH₂)₃ CH₃).

Examples of ester derivatives of a carboxy group represented by Ginclude esters formed with alcohols such as (1-6C)alkanols, for examplemethanol, ethanol, propanol and t-butanol; indanol; benzyl alcohol;adamantol; (1-6C)alkanoyloxy(1-4C)alkanols such as pivaloyloxymethanol;glycolamides; (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl alcohol; and(1-4C)alkoxycarbonyl(1-4C)alkanols.

Examples of amide derivatives of a carboxy group represented by Ginclude amides derived from amines such as (1-4C)alkylamines, forexample methylamine; di(1-4C)alkylamines, for example dimethylamine;(1-4C)alkoxy(1-4C)alkylamines such as methoxyethylamine; and amino acidssuch as glycine or an ester thereof.

Preferably G represents a carboxy group or a (1-4C)alkoxycarbonyl groupsuch as methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl.

Particular pharmaceutically acceptable salts include, for example, saltswith acids affording physiologically acceptable anions, such as saltswith mineral acids, for example a hydrogen halide (such as hydrogenchloride and hydrogen bromide), sulphuric acid or phosphoric acid, andsalts with organic acids, for example acetic acid and trifluoroaceticacid. Other pharmaceutically acceptable salts include, for example saltswith inorganic bases such as alkali metal and alkaline earth metal salts(for example sodium salts), ammonium salts, and salts with organicamines and quaternary bases forming physiologically acceptable cationssuch as salts with methylamine, dimethylamine, trimethylamine,ethylenediamine, piperidine, morpholine, pyrrolidine, piperazine,ethanolamine, triethanolamine, N-methylglucamine, tetramethylammoniumhydroxide and benzyltrimethylammonium hydroxide.

Particular compounds of the invention include, for example, allophanicacid derivatives of formula I, or pharmaceutically acceptable saltsthereof, in which, unless otherwise stated, each of the variable groupsR¹, R², R³, X¹, Q, X² and G have any of the meanings definedhereinbefore or in this section concerning particular compounds of theinvention:

(a) R¹ represents a group of formula II in which A is attached para tothe position where the group NR² CONR³ CO is attached and is selectedfrom aminomethyl, guanidino and R^(a) N═C(NH₂)-- where R^(a) is hydrogenor phenyl, g is CH or N, and Z¹ is hydrogen, fluoro, chloro, methyl,methoxy or cyano;

(b) R¹ represents a group of formula III in which T is CH or N, and X³is a bond, methylene, ethylene, trimethylene or, when T is CH,oxymethylene;

(c) R² and R³ which may be the same or different, represent hydrogen,methyl, ethyl or benzyl;

(d) X¹ is a bond or methylene;

(e) Q is a group of formula IV in which Z² is hydrogen, fluoro, chloro,methyl, methoxy or cyano, and Z³ is hydrogen or a group of formula X²--G^(a) in which X² is methylene, ethylene or oxymethylene and G^(a) isa carboxy group or a pharmaceutically acceptable metabolically labileester thereof;

(f) Q is a group of formula V in which Z³ is hydrogen or a group offormula X² --G^(a) in which X² is methylene, ethylene or oxymethyleneand G^(a) is a carboxy group or a pharmaceutically acceptablemetabolically labile ester thereof;

(g) X² is methylene, ethylene or oxymethylene; and

(h) G is a carboxy group or a pharmaceutically acceptable metabolicallylabile ester thereof.

A preferred compound of the invention is an allophanic acid derivativeof formula I wherein R¹ represents a group of formula II in which A isattached para to the position where the group NR² CONR³ CO is attachedand is selected from aminomethyl and a group of formula R^(a) N═C(NH₂)--where R^(a) is hydrogen or phenyl,

E is CH and Z¹ is hydrogen, fluoro, chloro, methyl or methoxy;

R² is hydrogen, methyl or benzyl;

R³ is hydrogen, methyl or benzyl;

X¹ is a bond;

Q is a group of formula IV in which Z² is hydrogen, fluoro, chloro,methyl or methoxy, and Z³ is hydrogen or a group of formula X² --G^(a)in which X² is oxymethylene and G^(a) is carboxy, methoxycarbonyl orethoxycarbonyl;

X² is oxymethylene; and

G is carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl ort-butoxycarbonyl;

or a pharmaceutically acceptable salt thereof.

A further preferred compound of the invention is an allophanic acidderivative of formula I wherein R¹ represents a group of formula III inwhich T is CH or N, and

X³ is a bond, methylene, ethylene or, when T is CH, oxymethylene;

R² is hydrogen, methyl or benzyl;

R³ is hydrogen, methyl or benzyl;

X¹ is a bond;

Q is a group of formula IV in which Z² is hydrogen, fluoro, chloro,methyl or methoxy, and Z³ is hydrogen or a group of formula X2--G^(a) inwhich X² is oxymethylene and G^(a) is carboxy, methoxycarbonyl orethoxycarbonyl;

X² is oxymethylene; and

G is carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl ort-butoxycarbonyl;

or a pharmaceutically acceptable salt thereof.

A further preferred compound of the invention is an allophanic acidderivative of formula I wherein R¹ represents a group of formula II inwhich A is attached para to the position where the group NR² CONR³ CO isattached and is a group of formula R^(a) N═C(NH₂)-- where R^(a) ishydrogen,

E is CH and Z¹ is hydrogen;

R² is hydrogen;

R³ is hydrogen or methyl;

X¹ is a bond;

Q is a group of formula IV in which Z² is hydrogen and Z³ is hydrogen ora group of formula X2--G^(a) in which X² is oxymethylene and G^(a) iscarboxy;

X² is oxymethylene; and

G is carboxy, methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl; or apharmaceutically acceptable salt thereof.

A further preferred compound of the invention is an allophanic acidderivative of formula I wherein R¹ represents a group of formula III inwhich T is CH and

X³ is ethylene;

R² is hydrogen;

R³ is hydrogen or methyl;

X¹ is a bond;

Q is a group of formula IV in which Z² is hydrogen and Z³ is hydrogen ora group of formula X2--G^(a) in which X² is oxymethylene and G^(a) iscarboxy;

X² is oxymethylene; and

G is carboxy, methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl;

or a pharmaceutically acceptable salt thereof.

Specific especially preferred compounds of the invention includeallophanic acid derivative of formula I selected from: methyl4-[4-(4-amidinophenyl)allophanoyl]phenoxyacetate and4-[4-(4-amidinophenyl)allophanoyl]phenoxyacetic acid; or apharmaceutically acceptable salt thereof.

The compounds of formula I, the metabolically labile esters and amidesthereof, and the pharmaceutically acceptable salts thereof may beprepared by procedures analogous to procedures known in the art for thepreparation of structurally analogous compounds. Such procedures areincluded as a further feature of the invention and include the followingpreferred procedures for the manufacture of a compound of the formula Iin which R¹, R², R³, X¹, Q, X² and G have any of the meanings definedabove:

(A) For a compound of formula I in which G is carboxy, deprotecting acompound of formula VI in which G¹ is a carboxy protecting group.

G¹ may be any conventional carboxy protecting group that may be removedwithout interfering with other parts of the molecule. Examples ofcarboxy protecting groups include (1-6C)alkyl groups (such as methyl,ethyl, propyl or t-butyl), phenyl and benzyl, the phenyl moiety in anyof which may optionally bear 1 or 2 of halogeno, (1-4C)alkyl,(1-4C)alkoxy or nitro.

The deprotection may be carried out using any one or more of theconventional reagents and conditions known in the art for convertingcarboxylic esters into carboxylic acids. Thus, for example, thedeprotection may conveniently be performed by base catalysed hydrolysis,for example by using an alkali metal hydroxide such as lithium,potassium or sodium hydroxide, or a tertiary amine such astriethylamine, in the presence of water. The base catalysed hydrolysismay conveniently be performed in the presence of a solvent such as analcohol, for example methanol or ethanol, or an ether such astetrahydrofuran or dioxan. Alternatively the deprotection may be carriedout by acid catalysed hydrolysis, for example using acetic acid ortrifluoroacetic acid. Suitable solvents for the acid catalysedhydrolysis include alcohols such as those mentioned above, halogenatedhydrocarbons such as dichloromethane, ethers such as anisole, and water.The temperature is conveniently in the range of from -10° to 100° C, forexample from 10° to 50° C. When the alcohol residue is t-butyl, this mayalso conveniently be removed by heating, for example at a temperature inthe range of from 80° to 150° C., alone or in the presence of a suitablediluent such as diphenyl ether or diphenyl sulphone.

It will be appreciated that a compound of formula I in which Grepresents carboxy and Q represents a group of formula IV or V whereinZ³ represents a group of formula X² --COOH may be prepared by thisprocess starting from a compound of formula VI in which Q represents agroup of formula IV or V and Z³ represents a group of formula X² --COOHor X² --COOG¹.

(B) For a compound of formula I in which R¹ is a group of formula II andA is an aminomethyl or an amidino group, deprotecting a compound offormula VII in which A¹ is a protected aminomethyl or amidino group.

A¹ may be any conventional protected aminomethyl or amidino group thatmay be deprotected without interfering with other parts of the molecule.Examples of protecting groups include oxycarbonyl groups such ast-butoxycarbonyl and benzyloxycarbonyl.

The deprotection may be carried out using any one or more of theconventional reagents and conditions known in the art for removing amineprotecting groups. A t-butoxycarbonyl group may be removed byhydrolysis, for example by acid catalysed hydrolysis using an acid suchas trifluoroacetic acid. Suitable solvents include halogenatedhydrocarbons such as dichloromethane. A benzyloxycarbonyl group mayconveniently be removed, for example, by hydrogenation in the presenceof a palladium catalyst such as palladium on charcoal. The temperatureis conveniently in the range of from -10° to 100° C., for example from10° to 50° C.

In some cases the reaction conditions required to perform process (A)are the same as those required to perform process (B). In such cases itis possible to perform processes (A) and (B) at the same time bystarting with a compound having an appropriate carboxy protecting groupand an appropriately protected aminomethyl or amidino group. Such acompound is represented by the formula VIII.

(C) For a compound of formula I in which R² and R³ represent hydrogenatoms, reacting an isocyanate of formula IX with an amine of formula X.

Suitable solvents include halogenated hydrocarbons such asdichloromethane and nitriles such as acetonitrile. The reaction isconveniently performed at a temperature in the range of from -10° to100° C.

(D) For a compound of formula I in which X² is a group of formula CH₂CH(NHXR⁴), reacting a compound of formula XI in which X^(2a) is CH₂CH(NH₂), or an acid addition salt thereof, with a compound of formulaXII in which U¹ is a leaving atom or group.

Examples of values for U¹ include halogen such as chlorine or bromineand hydrocarbylsulphonyloxy such as methanesulphonyloxy andp-toluenesulphonyloxy. Examples of acid addition salts include forexample, the hydrochloride. The reaction may conveniently be effected ata temperature in the range of from -10° to 120° C. preferably from 10°to 100° C. Suitable solvents include for example ethers such astetrahydrofuran, amides such as dimethylformamide, nitriles such asacetonitrile, halogenated hydrocarbons such as dichloromethane andalcohols such as ethanol. The reaction is conveniently performed in thepresence of a base, for example a tertiary amine such as triethylamine.

(E) For a compound of formula I in which R¹ is a group of formula II andA is a group of formula R^(a) N═C(NH₂)--, reacting a compound of formulaXIII, in which U² is a leaving atom or group, with a compound of formulaR^(a) NH₂, or an acid addition salt thereof.

Examples of values for U² include (1-4C)alkylthio groups such asmethylthio. Suitable media for the reaction include alcohols such asmethanol or ethanol, and halogenated hydrocarbons such asdichloromethane. The reaction is conveniently performed at a temperaturein the range of from -10° to 100° C. An acid addition salt of a compoundof formula R^(a) NH₂ may be for example an addition salt of an organicacid such as acetic acid or an inorganic acid such as hydrochloric acid.

The intermediates used in the aforementioned processes are either knownor may be prepared by methods analogous to methods known for preparingknown compounds. In general, the intermediates containing an acylureidogroup may be prepared by reacting the appropriate isocyanate derivativewith the appropriate amine.

Thus, the compounds of formula VI in which R² and R³ represent hydrogenmay be prepared by reacting an isocyanate of formula XIV with an amineof formula X by a method analogous to that of process (C) describedhereinabove.

The compounds of formula VI in which R¹ is a group of the formula II andA is an aminomethyl group may also be prepared by selectivelydeprotecting a compound of formula VIII. Similarily, the compounds offormula VII may also be prepared by selectively deprotecting a compoundof formula VIII.

The compounds of formula VIII in which R² and R³ represent hydrogen maybe prepared by reacting an amine of formula XV with an isocyanate offormula XIV following a method analogous to that of process (C)described hereinabove.

The compounds of formula IX and XIV may be prepared respectively byreacting a compound of formula XVI or XVII, or a protected derivativethereof, with oxalyl chloride. The reaction is conveniently effected ata temperature in the range of from -10° to 100° C. Suitable solventsinclude halogenated hydrocarbons such as dichloromethane and nitrilessuch as acetonitrile.

The compounds of formula XI in which R² and R³ are hydrogen may beprepared by a method analogous to process (C), by reacting an amine offormula X with an isocyanate of formula XVIII, or a protected derivativethereof, followed if necessary by the removal of the protectinggroup(s).

The compounds of formula XIII in which U² is a (1-4C)alkylthio group maybe prepared by reacting a compound of formula XIX with an alkylatingagent, for example a (1-4C)alkyl halide such as methyl iodide. Suitablemedia for the reaction include ketones such as acetone. Conveniently thereaction may be performed at a temperature in the range of from 0° to100° C.

The compounds of formula XIX may be prepared by reacting a compound offormula XX with hydrogen sulphide. The reaction is conveniently effectedin the presence of a base such as triethylamine and in the presence of asolvent such as pyridine.

The compounds of formula XX may be prepared by reacting an amine offormula XXI with an isocyanate of formula IX. Suitable solvents for thereaction include nitriles such as acetonitrile.

The compounds of formula XVIII may be prepared by reacting a compound offormula XXII, or a protected derivative thereof, with oxalyl chloride.Suitable solvents include halogenated hydrocarbons such as1,2-dichloroethane.

The compounds of formula I may be converted into pharmaceuticallyacceptable salts and/or metabolically labile esters or amides thereof bymethods well known in the art. For example, a pharmaceuticallyacceptable salt may be formed by reacting a compound of formula I withan acid capable of affording a physiologically acceptable anion, or abase capable of affording a physiologically acceptable cation. Apharmaceutically acceptable metabolically labile ester or amide may beformed respectively by esterifying a compound of formula I using aconventional technique, or by reacting an acid, or a reactive derivativethereof, with an appropriate amine. Similarly, when an optically activeform of a chiral compound of formula I is required, either one ofprocesses (A)-(E) above may be carried out using the appropriateoptically active starting material or else a racemic form may beresolved by a conventional procedure, for example, using an opticallyactive form of a suitable acid.

A suitable reactive derivative of an acid may be, for example, an acylhalide, for example an acyl chloride formed by the reaction of the acidand an inorganic acid chloride, for example thionyl chloride; a mixedanhydride, for example an anhydride formed by the reaction of the acidand a chloroformate such as isobutyl chloroformate; an active ester, forexample an ester formed by the reaction of the acid and a phenol such aspentafluorophenol or an alcohol such as 1-hydroxybenzotriazole; an acylazide, for example an azide formed by the reaction of the acid and anazide such as diphenylphosphoryl azide; an acyl cyanide, for example acyanide formed by the reaction of an acid and a cyanide such asdiethylphosphoryl cyanide; or the product of the reaction of the acidand a carbodiimide such as dicyclohexylcarbodiimide.

Many of the intermediates, for example compounds of formulae VI, VII,VIII, XI, XIII, XIX and XX are novel and form further aspects of thisinvention.

The ability of the compounds of formula I to inhibit plateletaggregation may be demonstrated using a standard test (a) based on thatdescribed by Born (Nature, 1962, 194, 927-929) and involving:

(i) aggregating human, citrated, platelet-rich plasma by addition ofadenosine diphosphate (ADP) so as to generate a dose-response curve;

(ii) generating a dose-response curve for ADP stimulated plateletaggregation in the presence of increasing amounts of a test compound(generally in the range 10⁻⁵ M to 10⁻¹⁰ M); and

(iii) calculating a pA₂ value indicating potency of platelet aggregationinhibition for the test compound, averaged over several concentrations,from the calculated 50% response value for ADP aggregation in thepresence and absence of the test compound.

Test (a) may be modified so as to assess the effects of a test compoundex vivo on the aggregation of human blood platelets after administrationof the test compound to a laboratory animal, such as a rat, rabbit,guinea pig, mouse or dog. For example, groups of four male, fastedAlderley Park Wistar rats are orally dosed with a test compound orappropriate vehicle, and at suitable time intervals (1, 3, 5 and 8 hoursafter dosing) animals are anaesthetised with fluothane and bled by heartpuncture. Blood is collected into 3.2% citrate (1 part to 9 parts wholeblood) and platelet poor plasma (ppp) prepared by centrifugation (4500×gfor 10 minutes).

Human blood is collected into 3.2% trisodium citrate (1 part to 9 partswhole blood) and centrifugated (200×g for 15 minutes) to produceplatelet rich plasma (prp).

Equal volumes (125 μl) of rat ppp and human prp are mixed together, ADPadded, and the whole incubated (37° C.) and stirred (900 rpm) in aBioData platelet aggregometer. Aggregation is induced with ADP andagonist EC₅₀ values calculated for human prp/rat ppp mixtures fromanimals dosed with test compound or vehicle. A mean concentration ratio(concentration of ADP required to cause a 50% aggregation response inhuman prp/rat ppp mixtures from animals dosed with antagonist, dividedby the concentration of ADP to cause 50% aggregation in human prp/ratppp mixtures from animals dosed with vehicle) is calculated at each timepoint.

The ability of the compounds of formula I to inhibit binding offibrinogen to GPIIb-IIIa may be demonstrated using the followingstandard test (b) involving:

(i) Preparation of human platelet lysates

Platelet rich plasma (prp) is harvested by centrifugation (1000 rpm, 15minutes) of whole blood anticoagulated with acid citrate dextrose(trisodium citrate 85 mM, citric acid 70 mM, d-glucose 110 mM) 1 part to6 parts blood. Prostacyclin (PGI₂, 1 μM) is added to the prp beforecentrifugation (2400 rpm, 15 min) and the resulting pellet isresuspended in modified Tyrodes' solution (NaCl 130 mM, KCl 26 mM,NaHCO₃, 12 mM, NaH₂ PO₄ 0.5 mM, MgCl₂ 1 mM, CaCl₂ 20 mM, Glucose 12 mM,HEPES 5 mM) containing bovine serum albumin 3.5 g/L, PGI₂ 1 μM andhirudin 0.5 U/ml. The platelet suspension is centrifuged (2400 rpm, 15minutes) and the resultant pellet resuspended in 500 μl of lysis buffer(octyl glucoside 50 mM, HEPES 10 mM, NaCl 150 mM, CaCl₂ 1 mM, MgCl₂ 1mM, PMSF 1 mM, NEM 10 mM, leupeptin 0.1 mM), agitated at 4° C. for 15minutes then centrifuged at 24000 rpm, 15 minutes. The supernatant isstored at 4° C. and the pellet re-suspended in 500 μl of lysis buffer.The centrifugation process is repeated a further 3 times, the pooledsupernatants being stored at -70° C.

(ii) Receptor purification

Glycoprotein IIb/IIIa is isolated from human platelet lysates using a 2ml peptide (KYGRGDS) coupled CNBr activated Sepharose affinity column. A1.5 ml volume of platelet lysate is placed on the column and allowed tostand overnight at 4° C. Buffer (30 ml, octyl glucoside 25 mM, HEPES 10mM, NaCl 150 mM, CaCl₂ 1 mM, MgCl₂ 1 mM, PMSF 1 mM, NEM 10 mM, leupeptin0.1 mM) is passed through the column and 2 ml fractions are collectedthroughout. GPIIb/IIIa is eluted with 12 ml of buffer containingHHLGGAKQAGDV (2mg/ml, pH 7.5), the column is washed using 4 ml bufferand the remaining GPIIb/IIIa eluted using 12 ml buffer containingGRGDSPG (1 mg/ml pH 7.5). The column is finally washed using 20 ml ofbuffer and can be used for up to three such preparations. Fractionscontaining GPIIb/IIIa are identified using gel electrophoresis andimmunoblotting, pooled and stored at -70° C.

(iii) GPIIb/IIIa ELISA

96 well microtitre plates are coated with 100 μl purified human plateletfibrinogen receptor (GPIIb/IIIa) diluted in coating buffer (Tris-HCl 20mM, NaCl 150 mM, CaCl₂ 1 mM, pH 7.4) and left overnight at 4° C. Theplates are washed using washing buffer (Tris-HCl 50 mM, NaCl 100 mM,CaCl₂ 2 mM, pH 7.4) and non-specific binding blocked by the addition of200μl 2% BSA (2 hours, 30° C.). The plates are washed prior toincubation (2 hours, 30° C.) with 100 μl biotinylated fibrinogen (10 nM)containing either vehicle or test compound. The plates are washed,incubated with streptavidin (5 μg/ml, 1 hour, ambient temperature), thenwashed again before the addition of 100 μl biotinylated horse radishperoxidase (0.1 μg/ml, 1 hour, ambient temperature). The plates are thenwashed and equal volumes of peroxidase substrate(3,3',5,5'-tetramethylbenzidine 0.4 g/l) and H₂ O₂ (0.02%) are mixedtogether immediately before addition of 150 μl to each well. Colour isallowed to develop for 10-15 minutes before optical densities are readat 650 nm.

    ______________________________________    Abbreviations    PMSF     Phenylmethylsulphonyl fluoride    HEPES    2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulphonic             acid    NEM      N-ethylmaleimide    ______________________________________

The concentration of compound required to cause 50% inhibition ofbiotinylated fibrinogen binding is calculated and expressed as a pIC₅₀(-log(IC₅₀)).

The compounds of formula I exemplified herein have been found to showeffects in the following ranges in at least one of the above tests:

test (a): pA₂ of>4.5

test (b): pIC₅₀ of>4.5

In general, it has been found that compounds of formula I in which G iscarboxy show a higher level of activity in test (a) and test (b) thanthose in which G is an ester group.

For example, the compound described in Example 1 hereinafter has beenfound to give a pA₂ of 7.5 in test (a) and a pIC₅₀ of 6.9 in test (b),whereas the compound of Example 2 has been found to give a pA₂ of 7.6 intest (a) and a pIC₅₀ of 7.6 in test (b).

As stated previously, the compounds of formula I may be used in thetherapy or prevention of diseases in which cell adhesion (especiallyplatelet aggregation) is involved, for example venous or arterialthrombosis (for example pulmonary embolism, stroke and thrombotic eventsaccompanying unstable angina and transient ischaemic attack), myocardialinfarction, migraine, atherosclerosis, thromboembolism and reocclusionduring and after thrombolytic therapy. The compounds may also be usefulfor the prevention of reocclusion or restenosis following percutaneoustransluminal coronary angioplasty (PTCA) and coronary artery bypassgraft. It will also be appreciated that the compounds may be useful inthe treatment of other diseases mediated by binding of adhesionmolecules to GPIIb/IIIa, for example cancer.

According to another aspect, therefore, the invention provides a methodof inhibiting platelet aggregation in a warm-blooded mammal requiringsuch treatment, which comprises administering an effective amount of acompound of formula I, or a pharmaceutically acceptable metabolicallylabile ester or amide thereof, or a pharmaceutically acceptable saltthereof.

According to yet another aspect, the invention provides a method ofinhibiting binding of fibrinogen to GPIIb/IIIa in a warm-blooded animalrequiring such treatment, which comprises administering an effectiveamount of a compound of formula I, or a pharmaceutically acceptablemetabolically labile ester or amide thereof, or a pharmaceuticallyacceptable salt thereof.

According to a further aspect, the invention provides the use of acompound of formula I, or a pharmaceutically acceptable metabolicallylabile ester or amide thereof, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for the prevention ortreatment of a disease involving platelet aggregation.

According to yet another aspect, the invention provides the use of acompound of formula I, or a pharmaceutically acceptable metabolicallylabile ester or amide thereof, or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for the prevention ortreatment of a disease involving binding of fibrinogen to GPIIb/IIIa.

In general, a compound of formula I will be administered for thispurpose by an oral, rectal, topical, intravenous, subcutaneous,intramuscular or inhalation route, so that a dose in the range of from0.01 to 50 mg/kg body weight will be given, depending upon the route ofadministration, the age and sex of the patient, and the severity of thecondition to be treated.

The compounds of formula I will generally be used in the form of apharmaceutical composition comprising a compound of formula I, or apharmaceutically acceptable metabolically labile ester or amide thereof,or a pharmaceutically acceptable salt thereof, together with apharmaceutically acceptable diluent or carrier. Such a composition isprovided as a further feature of the invention and may be in a varietyof dosage forms. For example, it may be in the form of tablets,capsules, solutions or suspensions for oral administration; in the formof creams or ointments or a transdermal (skin) patch for topicaladministration; in the form of a suppository for rectal administration;in the form of a sterile solution or suspension for administration byintravenous or intramuscular injection; in the form of an aerosol or anebuliser solution or suspension, for administration by inhalation; andin the form of a powder, together with pharmaceutically acceptable inertsolid diluents such as lactose, for administration by insufflation.Depending upon the route of administration, the composition will, ingeneral, comprise, for example, 1 to 99% by weight of a compound offormula I.

The pharmaceutical compositions may be obtained by conventionalprocedures using pharmaceutically acceptable diluents and carriers wellknown in the art. Tablets and capsules for oral administration mayconveniently be formed with an enteric coating, for example comprisingcellulose acetate phthalate, to minimise contact of the activeingredient of formula I with stomach acids.

The compounds according to the invention may be co-adminstrated orco-formulated with one or more agents known to be of value in diseasesor conditions intended to be treated; for example a known plateletaggregation inhibitor (e.g. aspirin, a thromboxane antagonist or athromboxane synthase inhibitor), hypolipidemic agent, anti-hypertensiveagent, thrombolytic agent (such as streptokinase, urokinase,prourokinase, tissue plasminogen activator and derivatives thereof),beta-adrenergic blocker or a vasodilator may usefully also be present ina pharmaceutical composition of the invention for use in treating aheart or vascular disease or condition.

In addition to their use in therapeutic medicine, the compounds offormula I are also useful as pharmacological tools in the developmentand standardisation of test systems for the evaluation of the effects ofadhesion molecules in laboratory animals such as cats, dogs, rabbits,monkeys, rats and mice, as part of the search for new therapeuticagents. The compounds of formula I may also be used because of theirplatelet aggregation inhibitory properties in helping to store blood andto maintain the viability of blood and blood vessels in warm-bloodedanimals (or parts thereof) under-going artificial extracorporealcirculation, for example during limb or organ transplants. When used forthis purpose a compound of formula I, or a pharmaceutically acceptablesalt thereof, will generally be administered so that a steady stateconcentration in the range, for example, 0.1 to 10 mg per liter isachieved in the blood.

The invention will now be illustrated by the following nonlimitingExamples in which unless otherwise stated:(i)

(i) concentrations and evaporations were carried out by rotaryevaporation in vacuo;

(ii) operations were carried out at ambient temperature, that is, in therange 18°-26° C.;

(iii) column chromatography was carried out on silica (Merck Art. 9385)available from E Merck and Co., Darmstadt, Germany;

(iv) yields are given for illustration only and are not necessarily themaximum attainable by diligent process development;

(v) proton NMR spectra were normally determined at 200 MHz or 250 MHz indimethylsulphoxide-d₆ using tetramethylsilane (TMS) as an internalstandard, and are expressed as chemical shifts (delta values) in partsper million relative to TMS using conventional abbreviations fordesignation of major peaks: s, singlet; m, multiplet; t, triplet; br,broad; d, doublet; and

(vi) ether refers to diethyl ether, DMSO to dimethylsulphoxide and TFAto trifluoroacetic acid.

EXAMPLE 1 Methyl 4-[4-(4-amidinophenyl)allophoyl]phenoxyacetate, acetatesalt

Ammonium acetate (1 g) was added to a stirred suspension of methyl4-[4-(4-methylthiocarbonimidoylphenyl)allophanoyl]phenoxyacetate,hydroiodide salt (340 mg), in methanol (6 ml) and dichloromethane (4ml). The reaction mixture was stirred at ambient temperature for 3 daysand then heated to reflux for 30 hours. The solvents were removed invacuo and the resultant solid residue was stirred under methanol for 1hour. The solid was collected and washed with methanol to give the titlecompound (249 mg) as a white solid; m.p. 225°-229° C. (decomposes); NMRSpectrum (DMSO-d₆) 1.75 (3H, s), 3.71 (3H, s), 4.92 (2H, s), 7.07 (2H,d), 7.80 (4H, s), 8.04 (2H, d); Mass Spectrum m/Z 371 (M+H)⁺ ; ElementalAnalysis: calculated for C₁₈ H₁₈ N₄ O₅. 1.0 CH₃ CO₂ H. 0.2 H₂ O: C,55.3%; H, 5.2%; N, 12.9%; found: C, 55.4%; H, 5.1%; N, 12.9%.

The necessary starting material was prepared as follows:

(a) To a stirred suspension of 4-methoxycarbonylmethoxybenzamide(preparation described in Bergeson, S. H. et al. (1986) European PatentApplication No. 189305 A2) (2.72 g) in 1,2-dichloroethane (50 ml) wasadded oxalyl chloride (2.2 ml). The reaction mixture was heated toreflux with stirring for 17 hours. The solvents were removed in vacuoand acetonitrile (30 ml) was added to the residue. Insoluble materialwas removed by filtration and the filtrate was added to a solution of4-aminobenzonitrile (1.54 g) and triethylamine (6.5 ml) in acetonitrile(100 ml) at ambient temperature. The reaction mixture was stirred for 1hour and the precipitated solid was collected, washed with acetonitrileand dried to give methyl 4-[4-(4-cyanophenyl)allophanoyl]phenoxyacetate(1.4 g) as a white solid; m.p. 204°-207° C.; NMR Spectrum (DMSO-d₆) 3.71(3H, s), 4.92 (2H, s), 7.08 (2H, d), 7.80 (4H, s), 8.03 (2H, d), 11.01(1H, s), 11.15 (1H, s); Mass Spectrum m/Z 354 (M+H)⁺.

(b) A mixture of the product of step (a) (600 mg), pyridine (56 ml) andtriethylamine (8 ml) was covered with a blanket of H₂ S gas and stirredat ambient temperature overnight. The dark green reaction mixture wasevaporated to dryness and the residue was stirred with dry ether for 1hour. The resultant solid was collected and washed thoroughly with etherto give methyl 4-[4-(4-thiocarbamoylphenyl)allophanoyl]phenoxyacetate(593 mg) as a yellow solid; m.p. 215°-218° C. (decomposes); NHR Spectrum(DMSO-d₆ +CD₃ CO₂ D) 3.73 (3H, s), 4.90 (2H, s), 7.08 (2H, d), 7.64 (2H,d), 7.98 (2H, d), 8.06 (2H, d); Mass Spectrum m/Z 388 (M+H)⁺.

(c) Iodomethane (5 ml) was added to a stirred suspension of the productof step (b) (550 mg) in acetone (50 ml). The reaction mixture wasstirred at ambient temperature for 2 days and then filtered. Thecollected solid was washed with acetone and dried to give methyl4-[4-(4-methylthiocarbonimidoylphenyl)allophanoyl]phenoxyacetate,hydroiodide salt (550 mg), as a yellow solid; m.p. 216°-219° C.(decomposes); NHR Spectrum (DMSO-d₆) 2.82 (3H, s), 3.71 (3H, s), 4.93(2H, s), 7.09 (2H, d), 7.91 (4H, m), 8.05 (2H, d), 11.08 (1H, s), 11.28(1H, s).

EXAMPLE 2 4-[4-(4-Amidinophenyl)allophanoyl]phenoxyacetic acid

To a stirred suspension of the product of Example 1 (100 mg) in methanol(25 ml) was added a 1% (by volume) solution of triethylamine in water(25 ml). The reaction mixture was stirred at ambient temperature for 24hours and filtered. The collected solid was washed thoroughly withmethanol and dried to give the title compound (60 mg) as a cream solid;m.p. 285°-288° C. (decomposes); NMR Spectrum (TFA+DMSO-d₆) 4.90 (2H, s),7.14 (2H, d), 7.90 (8H, m), 8.07 (2H, d); Mass Spectrum m/Z 357 (H+H)⁺ ;Elemental Analysis: calculated for C₁₇ H₁₆ N₄ O₅ : C, 53.5Z; H, 4.97%;N, 14.7; found: C, 53.6%; H, 4.8%; N, 14.6%.

EXAMPLE 3

Illustrative pharmaceutical dosage forms suitable for presenting thecompounds of the invention for therapeutic or prophylactic use includethe following, which may be obtained by conventional procedures wellknown in the art.

    ______________________________________    a)       Tablet I        mg/tablet             Active ingredient                             1.0             Lactose Ph. Eur.                             93.25             Croscarmellose sodium                             4.0             Maize starch paste                             0.75             (5% w/v aqueous paste)             Magnesium stearate                             1.0    b)       Tablet II       mg/tablet             Active ingredient                             50             Lactose         223.75             Croscarmellose sodium                             6.0             Maize starch    15.0             Polyvinylpyrrolidone                             2.25             (5% w/v aqueous paste)             Magnesium stearate                             3.0    c)       Tablet III      mg/tablet             Active ingredient                             100             Lactose         182.75             Croscarmellose sodium                             12.0             Maize starch paste                             2.25             (5% w/v aqueous paste)             Magnesium stearate                             3.0    (d)      Capsule         mg/capsule             Active ingredient                             10             Lactose Ph. Eur.                             488.5             Magnesium stearate                             1.5    (e)      Injection       mg/ml             Active ingredient                             1.0             (acid addition salt)             Sodium chloride 9.0             Purified water to 1.0 ml    ______________________________________     ##STR1##

We claim:
 1. A pharmaceutical composition comprising an allophanic acidderivative of formula I

    R.sup.1 --N(R.sup.2)CO--N(R.sup.3)CO--X.sup.1 --Q--X.sup.2 --GI

wherein R¹ represents a group of formula II or III ##STR2## in which Ais attached meta or para to the position where the group NR² CONR³ CO isattached and is selected from aminomethyl, guanidino and R^(a)N=C(NH₂)-- where R^(a) is hydrogen or phenyl which us unsubstituted orsubstituted by i or 2 of halogeno, (1-4C)alkyl, (1-4c) alkoxy, cyano andnitro, E is CH or N, Z¹ is hydrogen, halogeno, (1-4C)alkyl,(1-4C)alkoxy, cyano or nitro, T is N or CH, and X³ is a bond,(1-4C)alkylene or, when T is CH, oxy(1-3C)alkylene; R² and R³, which maybe the same or different, represent hydrogen, (1-4C)alkyl orar(1-4c)alkyl; X¹ is a bond or (1-4C) alkylene; Q is a group of formulaIv or V ##STR3## in which Z² is hydrogen, halogone, (1-4c)alkyl,(1-4C)alkoxy, cyano or nitro, and Z³ is a group of formula X² --G^(a) inwhich X² can have any of the values given hereinafter for X² and G^(a)can have any of the values given hereinafter for G, or G^(a) has any ofthe values given hereinbefore for Z² ; X² is a bond, (1-4C)alkylene,oxy(1-3C)alkylene or a group of formula CH₂ CH(NHXR⁴) in which X is SO₂,CO or CO₂ and R⁴ is (1-6C)alkyl, (6-12c)aryl or (6-12C)aryl(1-4C)alkyl,in any of which the aryl group may optionally be substituted by(1-4C)alkyl; and G is a carboxy group or a pharmaceutically acceptablemetabolically labile ester or amide thereof; and pharmaceuticallyacceptable salts thereof, together with a pharmaceutically acceptablediluent or carrier.
 2. The pharmaceutical composition of claim 1 whereinR¹ represents a group of formula II in which A is attached para to theposition where the group NR² CONR³ CO is attached and is selected fromaminomethyl and a group of formula R^(a) N═C(NH₂)-- where R^(a) ishydrogen or phenyl,E is CH and Z¹ is hydrogen, fluoro, chloro, methyl ormethoxy; R² is hydrogen, methyl or benzyl; R³ is hydrogen, methyl orbenzyl; X¹ is a bond; Q is a group of formula IV in which Z² ishydrogen, fluoro, chloro, methyl or methoxy, and Z³ is hydrogen or agroup of formula X² --G^(a) in which X² is oxymethylene and G^(a) iscarboxy, methoxycarbonyl or ethoxycarbonyl; . X² is oxymethylene; and Gis carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl ort-butoxycarbonyl;or a pharmaceutically acceptable salt thereof.
 3. Thepharmaceutical composition of claim 1 wherein R¹ represents a group offormula III in which T is CH or N, andX³ is a bond, methylene, ethyleneor, when T is CH, oxymethylene; R² is hydrogen, methyl or benzyl; R³ ishydrogen, methyl or benzyl; X³ is a bond; Q is a group of formula Iv inwhich Z² is hydrogen, fluoro, chloro, methyl or methoxy, and Z³ ishydrogen or a group of formula X² --G^(a) in which X² is oxymethyleneand G^(a) is carboxy, methoxycarbonyl or ethoxycarbonyl; X²oxymethylene; and G is carboxy, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl or t-butoxycarbonyl;or a pharmaceutically acceptablesalt thereof.
 4. The pharmaceutical composition of claim 1 wherein R¹represents a group of formula II in which A is attached para to theposition where the group NR² CONR³ CO is attached and is a group offormula R^(a) N═C(NH₂)-- where R^(a) is hydrogen,E is CH and Z¹ ishydrogen;. R² is hydrogen; R³ is hydrogen or methyl; X¹ is a bond; Q isa group of formula IV in which Z² is hydrogen and Z³ is hydrogen or agroup or formula X² --G^(a) in which X² is oxymethylene and G^(a) iscarboxy; X² is oxymethylene; and G is carboxy, methoxycarbonyl,ethoxycarbonyl or t-butoxycarbonyl;or a pharmaceutically acceptable saltthereof.
 5. The pharmaceutical composition of claim 1 wherein R¹represents a group of formula III in which T is CH andX³ is ethylene; R²is hydrogen; R³ is hydrogen or methyl; X¹ is a bond; Q is a group offormula IV in which Z² is hydrogen and Z³ is hydrogen or a group offormula X² --G^(a) in which X² is oxymethylene and G^(a) is carboxy; X²is oxymethylene; and G is carboxy, methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl;or a pharmaceutically acceptable salt thereof.
 6. Thepharmaceutical composition of claim 1 wherein the allophanic acidderivative of formula I is selected from: methyl4-[4-(-amidinophenyl)allophanoyl]phenoxyacetate and4-[4-(-amidinophenyl)allophanoyl]phenoxyacetic acid; or apharmaceutically acceptable salt thereof.
 7. A method of inhibitingplatelet aggregation is a warm-blooded mammal requiring such treatment,which comprises administering a platelet aggregation inhibitingeffective amount of an allophanic acid derivative of formula I

    R.sup.1 --N(R.sup.2)CO--N(R.sup.3)CO--X.sup.1 --Q--X.sup.2 --GI

wherein R¹ represents a group of formula II or III ##STR4## in which Ais attached meta or para to the position where the group NR² CONR³ CO isattached and is selected from aminomethyl, guanidino and R^(a)N═C(NH₂)-- where R^(a) is hydrogen or phenyl which us unsubstituted orsubstituted by 1 or 2 of halogeno, (1-4C)alkyl, (1-4c)alkoxy, cyano andnitro, E is CH or N, Z¹ is hydrogen, halogeno, (1-4C)alkyl,(1-4C)alkoxy, cyano or nitro, T is N or CH, and X³ is a bond,(1-4C)alkylene or, when T is CH, oxy(1-3C)alkylene; R² and R³, which maybe the same or different, represent hydrogen, (1-4C)alkyl orar(1-4C)alkyl; X¹ is a bond or (1-4c)alkylene; Q is a group of formulaIV or V ##STR5## in which Z² is hydrogen, halogeno, (1-4C)alkyl,(1-4C)alkoxy, cyano or nitro, and Z³ is a group of formula X² --G^(a) inwhich X² can have any of the values given hereinafter for X² and G^(a)can have any of the values given hereinafter for G, or G^(a) has any ofthe values given hereinbefore for Z² ; X² is a bond, (1-4c)alkylene,oxy(1-3C)alkylene or a group of formula CH₂ CH(NHXR²) in which X is SO₂,Co or CO₂ and R⁴ is (1-6c)alkyl, (6-12C)aryl or (6-12C)aryl(1-4C)alkyl,in any of which the aryl group may optionally be substituted by(1-4C)alkyl; and G is a carboxy group or a pharmaceutically acceptablemetabolically labile ester or amide thereof; and pharmaceuticallyacceptable salts thereof.
 8. The method of claim 7 wherein R¹ representsa group of formula II in which A is attached pard to the position wherethe group NR² CONR³ CO is attached and is selected from aminomethyl anda group or formula R^(a) N═C(NH₂)-- where R^(a) is hydrogen or phenyl,Eis CH and Z¹ is hydrogen, fluoro, chloro, methyl or methoxy; R² ishydrogen, methyl or benzyl; R³ is hydrogen, methyl or benzyl; X¹ is abond; Q is a group of formula IV in which Z² is hydrogen, fluoro,chloro, methyl or methoxy, and Z³ is hydrogen or a group of formula X²--G^(a) in which X² is oxymethylene and G^(a) is carboxy,methoxycarbonyl or ethoxycarbonyl; X² is oxymethylene; and G is carboxy,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or t-butoxycarbonyl;ore pharmaceutically acceptable salt thereof.
 9. The method of claim 7wherein R¹ represents a group of formula III in which T is CH or N,andX³ is a bond, methylene, ethylene or, when T is CH, oxymethylene; R²is hydrogen, methyl or benzyl; R³ is hydrogen, methyl or benzyl; X¹ is abond; Q is a group of formula IV in which Z² is hydrogen, fluoro,chloro, methyl or methoxy, and Z³ is hydrogen or a group of formula X²--G^(a) in which X² is oxymethylene and G^(a) is carboxy,methoxycarbonyl or ethoxycarbonyl; X² is oxymethylene; and G is carboxy,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl or t-butoxycarbonyl;ora pharmaceutically acceptable salt thereof.
 10. The method of claim 7wherein R¹ represents a group of formula II in which A is attached pareto the position where the group NR² CONR³ CO is attached and is a groupof formula R^(a) N═C(NH₂)-- where R^(a) is hydrogen,E is CH and Z¹ ishydrogen; R² is hydrogen; R³ is hydrogen or methyl; X¹ is a bond; Q is agroup of formula IV in which Z² is hydrogen and Z³ is hydrogen or agroup of formula X² --G^(a) in which X² is oxymethylene and G^(a) iscarboxy; X^(z) is oxymethylene; and G is carboxy, methoxycarbonyl,ethoxycarbonyl or t-butoxycarbonyl;or a pharmaceutically acceptable saltthereof.
 11. The method of claim 7 wherein R¹ represents a group offormula III in which T is CH andX³ is ethylene; R² is hydrogen; R³ ishydrogen or methyl; X¹ is a bond; Q is a group of formula IV in which Z²is hydrogen and Z³ is hydrogen or a group of formula X² --G^(a) in whichX² is oxymethylene and G^(a) is carboxy; X² is oxymethylene; and G iscarboxy, methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl;or apharmaceutically acceptable salt thereof.
 12. The method of claim 7wherein the allophanic acid derivative of formula I is selected from:methy 14-[4-(-amidinophenyl)allophanoyl]phenoxyacetate and4-[4-(-amidinophenyl)allophanoyl]phenoxyacetic acid; or apharmaceutically acceptable salt thereof.